2008 Brain Star Award Recipients - Edor Kabashi and Paul Valdmanis
Recipients
Edor Kabashi - Biosketch
Post-Doctoral Fellow
University of Montreal
And
Paul Valdmanis - Biosketch
PhD Human Genetics
McGill University
Article
Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F, Pradat PF, Camu W, Meininger V, Dupre N, Rouleau GA.TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis.Nat Genet. 2008 May;40(5):572-4. Epub 2008 Mar 30.
Significance of the paper
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that affects upper and lower motor neurons leading to paralysis and eventually death within 15 years and has a lifetime risk of 1:1000. Mutations in the SOD1 gene cause ALS in 1-2% of patients; however, the genetic cause for a large proportion of ALS patients remains unknown. Inclusion bodies that are present in the spinal cord of ALS patients have recently been shown to label intensely with antibodies against TDP-43. We sought to determine if patients with ALS have mutations in the TDP-43 gene. Thus, we screened the six exons of TDP-43 in 200 patients with ALS from Quebec and France and 380 ethnically matched controls. We identified eight missense mutations in nine patients. Seven of these mutations clustered around the C-terminal region of the protein which has been shown to be involved in hnRNP binding. Lymphoblast cell lines derived from ALS patients with TDP-43 mutations had a shortened form of the TDP-43 protein similar to what had been shown in extracts from TDP-43 positive inclusion bodies in ALS.
These results strongly demonstrate that mutations in TDP-43 can lead to ALS. This has enabled the current development of in vitro and in vivo models using these TDP-43 mutations in order to elucidate novel mechanisms of ALS pathogenesis and to propose therapy for ALS patients. An understanding of these genes that cause motor neuron degeneration in ALS will help provide insight into the role these genes play in motor neuron development and maintenance.